Frequency Therapeutics — Hearing Loss Regeneration

[Flamingo1]

Why disappointing?

No significant improvement in audiograms. Which contradicts their whole premise of hearing restoration via regeneration of hair cells. I'm sorry, but that was a big disappointment.

I am optimistic still especially with all the money being invested and that MIT is involved as well as Mass Eye and Ear, and the heavy weight biochemists they have working for them.

Not to be a pessimist, but throwing millions of dollars and the brightest minds at something does not guarantee success. Look at Alzheimer's.

Big bird was an optimist, though a fairly neurotic one.

Perhaps with more experimentation FX-322 results will improve. I don't see anything neurotic about that!

 

[F-u-T]

Could FX-322 become available much sooner outside of US through Astellas?

 

[Mr Mister]

Things are heading in a bad direction. Just like what I said before, another AM-101...

You are correct and it is very strange that so many people here are in denial about it. Hearing loss drug that has no impact on audiogram does not need "just some fine-tuning" but requires another 10+ years of development to make it work, if it will work at all.

 

[JohnAdams]

no impact

10 dB at 8 kHz is not no impact.

 

[Coleoptere]

What puzzles me is how they can measure significant improvements in Word Recognization compared to placebo without changes in audiograms.

 

[lobbypolice]

Audiogram tests for less than 50% of the human range of hearing.

 

[FGG]

Audiogram tests for less than 50% of the human range of hearing.

Exactly. Though up to 8000 Hz is the most important range for speech, higher frequencies help "fine tune" and provide further clarity.

 

[GregCA]

Audiogram tests for less than 50% of the human range of hearing.

That's a common misconception, due to the fact that we don't hear "linearly". Hearing tests usually cover 5 octaves from 250 Hz to 8 kHz. The "missing part" above 8 kHz is about 1 more octave.

Not that it's not important, but it is incorrect to represent it as 50%, even though it is technically true. There are more octaves that we are missing below the standard 250 Hz threshold of the test.

 

[Earing]

When I first joined this site I posted my mistrust of this study. I said the companies put out these vague leading positive statements "hinting" at the messiah of all drugs. They then have this golden period where they raise cash. Everyone said "Oh no not these guys, they are a private company."

So now we see they:
1: Put out a positive vague statement.
2: Raised a bunch of cash.
3: Are going public to raise more cash.
4: Test is now showing less than believable positive results.

I hope I was wrong but time will tell.

 

[Daniel Lion]

No significant improvement in audiograms. Which contradicts their whole premise of hearing restoration via regeneration of hair cells. I'm sorry, but that was a big disappointment.

Not to be a pessimist, but throwing millions of dollars and the brightest minds at something does not guarantee success. Look at Alzheimer's.

Perhaps with more experimentation FX-322 results will improve. I don't see anything neurotic about that!

Sorry,

I didn't mean you were neurotic. I was referring to the character on Sesame St. Sincere apology there Flamingo1.

I still remain optimistic. I am waiting for the next trial when more injections are given. I think that will be really telling. You may be right and I should lower my hopes and really start embracing the idea of hearing aids.

Again, sorry. My words came at wrong and I appreciate your comments and insight.

 

[Fabrikat]

It's disappointing not to have more conclusive results of success at the first attempt.

We'll need Phase 2b results to get a better handle on FX-322's efficacy, but even if it fails at that point, it may still not be over.

I recall reading reports of research into nano particle delivery of drugs into the inner ear by Prof. Andrew Wise at the Melbourne University Bionics Institute.

He believed drugs that can repair inner-ear nerve damage are already available, but that no-one has yet been able to find a way to get them into the inner ear in the quantity required to work.

His method injects little 'cake sprinkles' filled with the drug into the ear, which is released over a period of months. That's months! Not an hour or two.

So perhaps that's where the solution may lie. Keeping the goop in the cochlea long enough for it to take effect.

To lift the mood, on another note, we've still got Audion Regain's results to come. The news might be more hopeful there.

 

[Daniel Lion]

Hearing Restoration and Hair Cell Regeneration Symposium on October 8th in NYC.

I believe William McLean from Frequency Therapeutics will be speaking. I can't go, it is too far for me... but perhaps somebody could go who lives within striking distance. It could potentially be really informative. I need to check again, one may be able to purchase access through a "webinar".

I was just skimming over the thread @Hazel posted under Research News. One of the first quotes under the bio pharmacology section said it can take a drug 12 years from lab to patient and cost as much as 2.6 billion dollars... interesting.

On a personal note, I'd like to apologize again for getting carried away. My hearing loss is really bad, and I just need to push on and accept that. My emotions get the better of me. Thank you all for understanding.

 

[Coleoptere]

Audiogram tests for less than 50% of the human range of hearing.

Exactly. Though up to 8000 Hz is the most important range for speech, higher frequencies help "fine tune" and provide further clarity.

So then they should also have audiogrammed the Phase 1B patients for 8 kHz to 16 kHz before and after. That would proof that FX-322 is working but something in the delivery should be tuned like @JohnAdams suggested earlier. Think for example exposure time or other variations that would satured the lower frequencies as well. The upcoming 2A does not show that variation though.

 

[sakrt]

Don't think so. I don't think it would have mattered after cochlear implants anyway.

I don't understand the logic to this going on in 2017, when implant surgeries are known to further destroy the inner ear along with adding other possible complications.

Why not aim to work at regenerating the ear(s) of those with SNHL to it's healthier natural state first without doing invasive implants? Was this tried prior 2017? That makes more sense.

 

[Flamingo1]

On a personal note, I'd like to apologize again for getting carried away. My hearing loss is really bad, and I just need to push on and accept that. My emotions get the better of me. Thank you all for understanding.

No need to apologize, Daniel. You always bring up very good points and help to keep the discussion moving.

 

[Daniel Lion]

No need to apologize, Daniel. You always bring up very good points and help to keep the discussion moving.

Thanks Flamingo1.

 

[KJS]

I would imagine they tested cochlea implant patients first since the first phase as a safety test. I assume they figured that a person's ear was completely damaged already so they want to make sure the drug would not cause more issues.

The next phase will have patients that have stable SSNHL and testing efficacy at dosage levels and intervals will more closely aligned to what they are trying to solve.

I believe the IPO is a good sign. While not in pharmaceutical industry I have been with several tech companies that went from start-up to IPO and in order to go public they had to have shown technical solution with broad market acceptance in order for the investors to get behind. The IPO was NOT an exit but a new beginning. Both of those companies have gone on to become multi-billion revenue and gained significant market share since their IPOs.

If Frequency Therapeutics was trying to do something that not other animal species had ever proven to do then maybe the chance of success would be really low, but they know how other species do re-generate hearing. Humans have that same mechanism so I have to believe they will get it right... just when is the big question. I choose to stay bullish on them.

 

[Mr Mister]

10 dB at 8 kHz is not no impact.

That is not statistically significant. Most of the patients didn't get any impact on any of the tested frequencies.

I wanted them to succeed as much as you do but the audiogram results don't lie. They are trying to hide this fact by diverting attention to word scores which is pathetic.

 

[JohnAdams]

That is not statistically significant. Most of the patients didn't get any impact on any of the tested frequencies.

I wanted them to succeed as much as you do but the audiogram results don't lie. They are trying to hide this fact by diverting attention to word scores which is pathetic.

While this could actually be true, I think it is too early to make such a declaration.

"Quote da waben, NEBERMORE"
-Jan Terri

 

[FGG]

That is not statistically significant. Most of the patients didn't get any impact on any of the tested frequencies.

I wanted them to succeed as much as you do but the audiogram results don't lie. They are trying to hide this fact by diverting attention to word scores which is pathetic.

The word scores are not to be ignored, though. The p value was 0.01, which means these results were very unlikely to be due to chance.

One possible way to interpret this is that the drug works but doesn't diffuse far enough in the dose provided for the safety study (ie only frequencies higher than 8 kHz were involved except for those 4 who got 10 dB improvements).

Since the speech in noise scores also improved, it may have an even greater effect on synaptic connections than the hair cells. So many unknowns but with the p value provided, it is statistically unlikely the drug has no effect on hearing.

 

[JohnAdams]

The word scores are not to be ignored, though. The p value was 0.01, which means these results were very unlikely to be due to chance.

One possible way to interpret this is that the drug works but doesn't diffuse far enough in the dose provided for the safety study (ie only frequencies higher than 8 kHz were involved except for those 4 who got 10 dB improvements).

Since the speech in noise scores also improved, it may have an even greater effect on synaptic connections than the hair cells. So many unknowns but with the p value provided, it is statistically unlikely the drug has no effect on hearing.

Do we know if they even tested higher frequencies than 8 kHz? That's a super question right there because if they didn't, then there could have been significant increases which would easily explain the word recognition scores.

 

[FGG]

Do we know if they even tested higher frequencies than 8 kHz? That's a super question right there because if they didn't, then there could have been significant increases which would easily explain the word recognition scores.

My hunch is it's unlikely they tested the higher frequencies.

Per the otologist I saw at Hough, the reason most audiograms are only up to 8 kHz is not just because of the limitations of hearing aids, but it's much more difficult to calibrate that high. That's why only a few centers offer it. If the trial took place at centers that didn't offer high frequency audiograms *or* if the patients didn't have a baseline before treatment (very likely the case) because they didn't have the higher values as part of the safety trial design, then you couldn't get this information. Above 8000 Hz is not part of a standard audiogram, even in most big name centers, so you couldn't even base your trial participant selection on it.

It's interesting that up to 16000 Hz is part of the investigational part of the next trial though.

 

[RB2014]

I hope they didn't use the same words from the first test to the second after the injections... If you take one word score test, you naturally do better on the second because you know what to expect. If you know what words to expect it just made it a whole lot easier... Even the placebo group scored better on the word scores the second time... The control group did have better scores than the placebo group so that is a good sign. Agreed that the higher frequencies help fine tune wording understanding. Maybe 8 to 16 kHz saw some improvement.

I'll stay optimistic, but I'm a lot more grounded after reading those results. I was really hoping for something better on the audiogram test.

Did anyone read the risks on the IPO... Ouch.

 

[Coleoptere]

@JohnAdams: That's the major Q indeed. An easy test by the way which they should have included provided they didn't.

 

[Coleoptere]

The word scores are not to be ignored, though. The p value was 0.01, which means these results were very unlikely to be due to chance.

One possible way to interpret this is that the drug works but doesn't diffuse far enough in the dose provided for the safety study (ie only frequencies higher than 8 kHz were involved except for those 4 who got 10 dB improvements).

Since the speech in noise scores also improved, it may have an even greater effect on synaptic connections than the hair cells. So many unknowns but with the p value provided, it is statistically unlikely the drug has no effect on hearing.

You are spot on

 

[andreimatei]

Guys, I think there is cause for optimism here. I know we all wanted to see massive improvements in audiograms, but we aren't there yet without more doses. I think the below quotes from the findings are important. And, if they weren't on to something here, would they really be moving towards IPO?

"We believe that FX-322 has the potential to meaningfully improve overall hearing function and significantly enhance quality of life for patients with hearing loss."

"We also performed a post hoc analysis that showed a statistically significant improvement in WR by all FX-322-treated patients versus all placebo patients (p=0.01)"

"FX-322 treated patients saw improvements as early as 15 days after treatment that were sustained over 90 days."

And it seems to work for hearing loss caused by ototoxic meds as well (at least in mice) and not just sound-induced...

"To cause hair cell loss, we exposed the cochlea for 16 hours to an aminoglycoside antibiotic that is toxic to hair cells. We then treated the cochlea for 72 hours with the compounds comprising the active agents in FX-322. Aminoglycoside treatment (left panel in the figure below) killed more than 80% of the hair cells in the cochlea (shown in green). By contrast, cochlea treated with the compounds in FX-322 (shown in the middle panel) regenerated hair cells to a near native level, as shown graphically in the right panel."

It's also helpful to know that we'll have phase 2a results second half of 2020. I guess we won't know if they are gonna go 2b or 3 until that time.

Someone call me out if you don't view this as cautiously positive!

 

[jeff W]

We are only human, prone to mistakes, that is why we all need each other in an honest and humble manner, forgiving, and able to accept our own missteps and ignorance. I am of a firm belief that if we would honestly come together in confidence and due diligence that this community could be a strong area of research. What we need to accept is that we have an ability to research despite a lack of degree or pedigree whatever. You guys already know I put much energy into this regardless of a clear-cut path to success.

TRY TRY TRY

https://clinicaltrials.gov/ct2/show/NCT03300687
View attachment 31804

They are years ahead in ear research and clinical testing. Only dedicated MD lab in the world.

 

[Mr Mister]

The word scores are not to be ignored, though. The p value was 0.01, which means these results were very unlikely to be due to chance.

One possible way to interpret this is that the drug works but doesn't diffuse far enough in the dose provided for the safety study (ie only frequencies higher than 8 kHz were involved except for those 4 who got 10 dB improvements).

Since the speech in noise scores also improved, it may have an even greater effect on synaptic connections than the hair cells. So many unknowns but with the p value provided, it is statistically unlikely the drug has no effect on hearing.

I am not sure exactly what kind of word score tests they used but I have completed them in the past and my experience is that there is a learning curve involved. At first you don't answer unless you are totally certain what you hear. Then after multiple tests you start to figure out what type of words get repeated and you become better at guessing through process of elimination.

I hope there was some hidden improvement in hearing that doesn't show in audiograms but that feels almost like defying the laws of physics.

 

[Mr Mister]

Do we know if they even tested higher frequencies than 8 kHz? That's a super question right there because if they didn't, then there could have been significant increases which would easily explain the word recognition scores.

This is what Wikipedia says about human speech frequency: "The voiced speech of a typical adult male will have a fundamental frequency from 85 to 180 Hz, and that of a typical adult female from 165 to 255 Hz. Thus, the fundamental frequency of most speech falls below the bottom of the "voice frequency" band as defined above. However, enough of the harmonic series will be present for the missing fundamental to create the impression of hearing the fundamental tone."

Highest note in a guitar is 988 Hz and that is really high. Some talented sopranos might also reach that note.

So it is not likely that 8000 Hz and above has material impact on understanding human voice. Let's assume we have a person that has 70 dB hearing loss through all frequencies. Then we improve his hearing between 8000-16000 Hz by say 20 dB. It is hard to say what could the impact be on hearing words but I don't think it's much. Those frequencies are so high that even my computer struggles to play them when I listen to the Hz test tones on YouTube.

 

[KJS]

I hope they didn't use the same words from the first test to the second after the injections... If you take one word score test, you naturally do better on the second because you know what to expect. If you know what words to expect it just made it a whole lot easier... Even the placebo group scored better on the word scores the second time... The control group did have better scores than the placebo group so that is a good sign. Agreed that the higher frequencies help fine tune wording understanding. Maybe 8 to 16 kHz saw some improvement.

I'll stay optimistic, but I'm a lot more grounded after reading those results. I was really hoping for something better on the audiogram test.

Did anyone read the risks on the IPO... Ouch.

If you have read an IPO prospectus they are usually overly cautious on risk indicators. They have to be to avoid litigation to investors. Kind of like side effect indicators to most medicines.